Proper organ development and size control require an intricate balance between cell proliferation and apoptosis in addition to cell differentiation. Central to such tissue homeostasis lies the Hippo pathway, which derives its name from the phenotypic resemblance of tissue overgrowths due to genetic mutations in Drosophila. Study of the mutated genes responsible for such growths led to discovery of the Hippo core signaling cassette consisting of Warts (Wts), Salvador (sav), Hippo (hpo), and Mob as tumor suppressor (mats) as the central kinases [15]. The transcriptional executor of the Hippo core kinases is subsequently discovered to be mediated by yorkie (yki) and its interacting partner Scalloped (sd). In mammals, the Hippo pathway is conserved: consisting of MST1/2 kinases (hpo ortholog) having scaffold protein WW45/SAV1 (sav ortholog) and LATS1/2 kinases (wts ortholog) having scaffold protein MOB1 (mats ortholog) as the central core kinases. Upon phosphorylation by MST1/2, activated LATS1/2 then phosphorylates YAP (Yes-associated protein) (yki orthology) and its paralog TAZ/WWTR1 to sequester them in the cytoplasm and/or promote their degradation. In the nucleus, YAP and TAZ act as transcriptional coactivators for TEAD1-4 (SD orthology) transcription factors binding to the promoter and enhancer regions of the target gene to drive their transcription to promote proliferation and inhibit apoptosis. In general, YAP/TAZ are functionally oncogenic, whereas Hippo core kinases and upstream activators (such as NF2, Amot protein, Kibra/WWC1) are tumor suppressive. Recently, MAP4Ks (with NF2 as HPO2 module) is proposed to act as kinases acting in parallel with MST1/2 (with WWC1-3 as HPO1 module) to activate LATS1/2 [17], although they are likely integrated by other regulators such as TAOK1-3 [18], STRIPAK phosphatase, which may inactivate both MST1/2 and MAP4Ks [14,16,17], and other players such as Amot proteins, tankyrase [19], actin cytoskeleton, and its regulator Rho GTPase [15]. Figure 1 serves as a working model of the Hippo signaling network.

The balance between activation of Hippo signaling and YAP/TAZ is extremely vital, especially when a myriad of Hippo-activating cues can be received at any one time. These include cell polarity, mechanical cues, stress signals and soluble factors [15]. The Hippo pathway is tightly regulated at multiple layers, including post-translational modifications (PTMs) and feedback signals [20]. Such dynamic regulations allow the cells to fine tune their response appropriately in a spatiotemporal manner. Imbalance in Hippo regulations is often pathological. For instance, Hippo core kinases are often found to be repressed in many cancers [21]. Therefore, the Hippo pathway offers an attractive pool of therapeutic targets for cancer. In this review, we will discuss latest discoveries in the Hippo pathway, focusing mainly on biomolecular condensate regulation of Hippo pathway components, and their roles in cancer. We will discuss mechanisms and explore how YAP/TAZ-TEAD interaction can be targeted for therapeutics.